In developed nations, the prevalence of obesity and its associated comorbidities continue to prevail despite the availability of numerous treatment strategies. Accumulating evidence suggests that multiple inputs from the periphery and within the brain act in concert to maintain energy metabolism at a constant rate. At the central level, the hypothalamus is the primary component of the nervous system that interprets adiposity or nutrient-related inputs; it delivers hormonal and behavioral responses with the ultimate purpose of regulating energy intake and energy consumption. At the molecular level, enzymes called nutrient energy sensors mediate metabolic responses of those tissues involved in energy balance ( 1 ). Two key energy/nutrient sensors, mammalian target of rapamycin and AMP-activated kinase, are involved in the control of food intake in the hypothalamus as well as in peripheral tissues ( 2 , 3 ). The third more recently discovered nutrient sensor, Sirtuin1 (Sirt1), a nicotinamide adenine dinucleotide-dependent deacetylase, functions to maintain whole-body energy homeostasis. Several studies have highlighted a role for both peripheral and central Sirt1 in regulating body metabolism, but its central role is still heavily debated. Owing to the opaqueness of central Sirt1's role in energy balance are its cell-specific functions. Because of its robust central expression, targeting cell-specific downstream mediators of Sirt1 signaling may help to combat obesity. However, when placed in the context of a physiologically relevant model, there is compelling evidence that central Sirt1 inhibition in itself is sufficient to promote negative energy balance in both the lean and diet-induced obese state.